Polyethylene glycol (PEG) is considered to be the polymer with the lowest level of protein and cell absorption in known polymers, and it has advantages of good water solubility and biocompatibility, no toxicity, no immunity, no teratogenicity and no antigenicity, and is widely used in drug modification, agent preparation and medical materials and other fields. Since 1991, after the first PEG-modified drug PEG-ADA was approved by the FDA, the major pharmaceutical companies have put a great interest in research and development of PEG in the field of drug. In recent years, the products on the market include PEG-somatostatin, PEG-interferon, PEG-granulocyte colony stimulating factor, etc. At present, there are further dozens of PEG-modified drugs which are in the process of research or clinical trial.
Although PEG has a unique advantage in the field of drug modification, it has some shortcomings: 1) PEG is a polymer product, which is a mixture that has a defect of heterogeneity in itself, which may not only limit the use of PEG, e.g., when PEG is used to modify the superoxide dismutase, a series of heterogeneous products may be produced (Characterization of the heterogeneity of polyethylene glycol-modified superoxide dismutase by chromatographic and electrophoretic techniques, JSnider et. al., Journal of Chromatography A 1992, 599, 141-155); but also bring some difficulties for the consistency between different batches of products and the validation of final product in drug synthesis; 2) linear PEG molecules has a high molecular weight, but can only connect the drug at both ends, inevitably resulting in decreased drug loading capacity.
In order to overcome the adverse effects of PEG, Dhawan et al. (Synthesis of polyamide oligomers based on 14-amino-3,6,9,12-tetraoxatetradecanoic acid, Dhawan et. al., Bioconjugate Chemistry 2000, 11, 14-21) prepared a linear discrete polyethylene glycol having the same structure with PEG (i.e., PEG with a defined molecular weight) and a derivative thereof by the reaction of sodium alkoxide with sulphonate in an organic synthesis process. The discrete polyethylene glycol has the same chemical formula as PEG, but the two are not identical, e.g., PEG12 and EG12 (dodecaethylene glycol), the former being a mixture of EG11, EG12, EG13 and longer or shorter polyethylene glycol, and the latter being a definite compound containing only EG12.
Although linear discrete polyethylene glycol solves the problem that PEG itself is not heterogeneous, it itself brings new problems. It preparation method requires protecting one end of the discrete polyethylene glycol at first and performing Williamson synthesis under strictly anhydrous conditions and then deprotecting to obtain discrete ethylene glycol with a longer chain segment. The synthesis method involves many steps, complicated operation and harsh conditions, requires strictly anhydrous conditions to get sodium alkoxide, and needs to use hydrogen for reduction in deprotection, which may limit its further spread and wide use, and although the loading capacity of polyethylene glycol with a relatively short chain segment has been improved, the water solubility is also significantly reduced, which may make its application range greatly limited.
In order to solve the drawbacks of the prior art, the present invention provides a Y-type discrete polyethylene glycol derivative and a preparation method thereof.